Transdermal and topical drug dosage forms have been widely prescribed for decades in the treatment of systemic diseases and local conditions such as those involved with the skin and underlying tissues. These drugs are typically “easy-to-deliver” since they freely permeate through the skin or mucosal membrane with a high potency. Permeation of the drug across the skin or mucosal membrane is a result of the chemical concentration gradient across the membrane. Examples of “easy-to-deliver” drugs include nitroglycerin, scopolamine, nicotine, hydrocortisone, betamethasone, benzocaine, and lidocaine.
Most drugs and biological active ingredients, however, do not easily permeate membranes and, therefore, are categorized as “difficult-to-deliver” drugs. Examples of “difficult-to-deliver” drugs include insulin, vasopressin, erythropoietin, interferons, and growth hormone and its releasing factors. Typically, “difficult-to-deliver” drugs have high hydrophilicity and/or high molecular weight, such as polypeptides, proteins, and polynucleotides (e.g., genes). To increase skin permeation of these drugs, various chemical and physical permeation enhancing methods have been employed. This process, however, is usually only effective for drugs having relatively low molecular weights (e.g., less than approximately 1000 daltons).
Electricity may be employed to facilitate drug transport across the membranes barrier by applying an electric potential gradient across the membrane to facilitate drug transport. There are three such types of electrically facilitated drug transport methods, namely, iontophoresis, electro-osmosis, and electroporation. In iontophoresis, an ionized drug is driven across the membrane by an applied electric potential gradient. In electro-osmosis, a non-ionic or poorly ionized drug is carried by a fluid that is driven across the membrane by an applied electric potential gradient. Electro-osmosis can also be used to extract interstitial fluid out of a body for diagnostic purposes. This process is called “reverse iontophoresis.” Electroporation is a process of creating transient microscopic pores on a barrier membrane, by extremely short pulses of high electric voltage and low current. U.S. Pat. Nos. 5,019,034, 5,547,467, 5,667,491, and 5,749,847 describe an “electroporation” method of treating a tissue in order to transiently increase the tissue's permeability to enhance molecular transport either for drug delivery or for sampling of interstitial fluids. All three of these transport methods are described by Sun in “Skin Absorption Enhancement by Physical Means: Heat, Ultrasound, and Electricity,” Transdermal and Topical Drug Delivery Systems, Interpharm Press, Inc., 1997, pages 327-355.
Although the above electrical methods can provide a powerful driving force for transdermal drug delivery, perforation of barrier membranes (e.g., the stratum corneum of the human skin) is still desirable to further facilitate drug transport. The following references disclose the disruption of the skin barrier membranes with mechanical means, i.e., with either small blades (i.e., microblades) or needles (i.e., microneedles): PCT Patent Applications WO 98/11937 and WO 97/48440; U.S. Pat. Nos. 5,250,023 and 5,843,114; and Henry et al., “Microfabricated Microneedles: A Novel Approach to Transdermal Drug Delivery”, S. Henry, D. V. McAllister, M. G. Allen and M. R. Prausnitz, Journal of Pharmaceutical Sciences, Vol. 8, August 1998, pages 922-925.
As an alternative approach, U.S. Pat. No. 5,885,211 describes a method of enhancing the permeability of the skin utilizing microporation by using a hot metal wire heated by electric current. The disclosed “hot-wire” method for stratum corneum ablation comprises an ohmic heating element, namely, a material with high electric resistance that is heated up to very high temperature when an electric current passes through it. This “hot-wire” method described in this patent is similar to electrocautery commonly used in surgery to stop bleeding.
Radio Frequency (“RF”) electric current has been used in electrosurgery for various surgical procedures. Electrosurgical machines produce high frequency alternating currents with frequencies of 500 kHz-4000 kHz. These frequencies are part of the low RF range and produced by oscillating circuits. Advantages of electrosurgery, in comparison to other surgical techniques, include simplicity of the technique, high speed, compact equipment, good safety, and applicable to both benign and malignant lesions.
Electrosurgery is different from electrocautery. In eletrocautery, a metal wire that becomes heated as a result of its high resistance to the passage of direct current electricity is used to cut the tissue. The electric current does not pass through the tissue of a patient under treatment, but rather only through the high resistance wire (the ohmic element) in order to heat it up. On the contrary, electrosurgery equipment, capable of producing RF electric current, are used to move or destroy tissue via a “cold” electrode, as described by S. V. Pollack, “Electrosurgery”, in Dermatology, Ed. S. L. Moschella and H. J. Hurley, W. B. Saunders Company, 1992, pages 2419-2431). In electrosurgery, the RF current passes through the patient tissue to produce intended heat to cause tissue disruption.
Previously published information regarding use of RF current in electrosurgery field has primarily been focused on the cutting and removing living tissues. The cutting depth is usually well into and often beneath the dermal tissues in dermatological and other surgeries. In contrast, the present invention relates to the novel use of electric current to ablate a barrier membrane (e.g. the stratum corneum of the human skin) to both enhance drug delivery for therapeutic purposes and enable sampling of biological substances for diagnostic purposes.
Previous references have used invasive electrode arrays or electrode matrices to create multiple points of disruption within the skin and in particular the stratum corneum. All of these devices have used either electroporation or electrofusion. U.S. Pat. No. 6,148,232 discloses a device for ablating the stratum corneum epidermidis of a subject, including a plurality of electrodes, which are applied to the subjects skin at respective points. U.S. Pat. No. 6,117,660 discloses a method for treating biological cells with pulsed electrical fields to induce pore formation in the cells. U.S. Pat. No. 5,993,434 discloses an apparatus that provides an effective and convenient means for positioning electrodes into tissue for the injection of therapeutic compounds into the tissue and application of electric fields to the tissue.
Other references, including U.S. Pat. Nos. 6,068,650, 5,869,326, 6,181,964, 6,120,493, 6,055,043, 6014,584, and 6,096,020, discuss the use of electroporation and multi-needle or multi-electrode array devices to penetrate internal organs for the treatment of cancerous growths. The present disclosed device utilizes electroperforation which is a non-contact, noninvasive, longer-term means of ablating or generating pores in the skin, particularly the stratum corneum.